Adenosine acts via specific, membrane-bound receptors to modulate the activity of the central nervous system. Little is known about the developmental appearance of adenosine receptors, or the effects of adenosine receptor manipulation during brain development. The experiments in this proposal will test two hypotheses: (1) a functional adenosine receptor systems are present in fetal rat brain, and (2) manipulation of adenosine receptors during development alters gene expression in the fetal striatum. The development of sensitivity to adenosine in the brain will be documented by studying expression of adenosine receptor mRNAs by Northern blot and in situ hybridization, adenosine receptor binding using ligand autoradiography, and adenosine receptor-mediated effects on adenylyl cyclase activity in vitro. Subsequent studies will examine the anatomical relationship between proenkephalin-expressing and A2a-adenosine receptor-expressing cells in the developing striatum. Finally, adenosine receptor manipulation with the antagonist, caffeine, will be performed to examine whether adenosine receptor regulate gene expression in the fetal striatum. Collectively, the experiments in this proposal will document the sensitivity of the fetal brain to adenosine, and provide an initial examination of the effects of adenosine receptor manipulation on striatal development. In the adult brain, adenosine modulates neurotransmitter release and electrical activity. These events are likely important in establishing and maintaining synaptic connections in the developing brain. Thus, adenosine and adenosine receptors may play important roles in the normal development of the nervous system. Prenatal alterations in adenosine receptor function may subtly alter these important neuronal interactions, contributing to the genesis of learning disabilities and other disorders of nervous system function.